The human CD2 molecule is found on virtually all T cells and thymocytes as well as natural killer cells, and it binds to the surface glycoprotein CD58 which is present on many cell types including antigen presenting cells. Human CD2 functions to facilitate both adhesion and activation of T lymphocytes on binding to CD58 (Bierer et al., Annu. Rev. Immunol. 7:579–599 (1989); Moingeon et al., Immunol. Rev. 111:111–133 (1989); Springer, Nature (London) 346:425–434 (1990)). Moreover, the binding of CD58 to CD2 augments interleukin (IL)-12-driven T cell responsiveness (Gollob et al., J. Exp. Med. 182:721–731 (1995); Gollob et al., J. Immunol. 157:1886–1893 (1996)) and initiates reversal of the anergic state (Boussiotis et al, J. Exp. Med. 180:1665–1673 (1994)). Although the important contribution of the cytoplasmic tail of CD2 to T cell activation has been studied in both rodents and humans (Chang et al., J. Exp. Med. 169:2073–2083 (1989); Chang et al., J. Exp. Med. 172:351–355 (1990); Bierer et al., J. Immunol. 144:785–789 (1990); He et al., Cell 54:979–984 (1988)), the mechanisms by which the CD2 tail mediates those functions are not clear.